Therapeutic Biomarkers in Lung Neuroendocrine Neoplasia

Abstract

The well known classification of neuroendocrine neoplasms of the lung into four major subtypes (including typical and atypical carcinoids and small and large cell neuroendocrine carcinomas) has a proven prognostic validity, but only partially helps to predict the response to specific therapies.Therapeutic biomarkers are incompletely known and include morphological, immunophenotypic and molecular markers. Morphology alone has no specific predictive role, nor has any immunophenotypic marker been proven to bear predictive implications. Ki67 is a relevant prognostic marker and can indirectly predict response to chemotherapy, when levels are extremely high in high-grade NE carcinomas. The expression of somatostatin receptors especially of the type 2A, has been shown to predict response to somatostatin analog treatments, paralleling the information derived from octreotide scintigraphy. mTOR pathway is targeted by specific inhibitors, but the exact cellular molecules predicting response are still to be defined. It seems that high levels of phosphorylated forms of mTOR and of its downstream factor S6K are associated to a better response to rapalogs in experimental models. Data from gene expression profiling and mutational analyses are currently emerging, providing a more detailed map of different molecular activation pathways, potentially leading to a more accurate molecular classification of lung NE tumors as well as to the discovery of new therapeutic targets. The combination of mutational profiles with those of up-or down-regulated genes also by gene gains or losses may ultimately provide a better characterization of NE tumor histological types in terms of response to specific chemo-or bio-therapies.

Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied

“…However, when diagnosing lung NET, a distinction has to be made between low-to intermediate-and high-grade NET even when biopsies are small or crushed, to avoid errors in patient management and provide appropriate treatment adapted to the intrinsic aggressiveness of the disease which often cannot be done by morphology only [1,20,21,31,33,38]. TC or AC is treated with somatostatin analogs, m-TOR pathway inhibitors, and/or peptide receptor radionuclide therapy (PRRT) [1,4,[42][43][44][45], once imaging, symptoms, tumor burden, individual risks of evolving disease, and actionable targets have been accounted for [1,21]. Once SCC has been ruled out, metastatic NETs are treated with PRRT or alkylating-based chemotherapy, to avoid the side effects of platinum/ etoposide [42,45].…”

Bi-directional roles of IRF-1 on autophagy diminish its prognostic value as compared with Ki67 in liver transplantation for hepatocellular carcinoma

“…Ki67 is a well-known biomarker for cell proliferation, and correlates with the prognosis of malignant tumors [17–19]. IRF-1 is described as the “master promoter”, as it is involved in tumor growth regulation through a variety of mechanisms [2, 20–24].…”

Systemic treatment for lung carcinoids: from bench to bedside

“…These data might suggest that lung carcinoids and poorly differentiated neuroendocrine tumors of the lung (SCLC and LCNEC) represent two separate entities rather than a continuum of diseases ranging from well to poorly differentiated forms [44, 45]. Besides IHC staining, further in vitro techniques can be utilized to detect SSTRs; moreover, octreotide scintigraphy (SRS) and PET with Ga68-radiolabeled-peptides seem to correlate with IHC expression of SSTRs providing a non-invasive evaluation of this therapeutic biomarker [13].…”

“…MEN1 maps on chromosome 11 and encodes for menina, a nuclear protein involved in cell replication, DNA repair and transcription process. Mutation or loss of this gene can be found in 13% of sporadic pulmonary carcinoids and seem to be associated to shorter survival [13]. Furthermore, almost 5% of patients with lung carcinoids have MEN1 syndrome harboring a germinal mutation of this gene; in these cases, family history, clinical examination and laboratory tests like calcium, parathyroid hormone (PTH) and prolactin should be performed as well as a screening for mutational analysis [14–16].…”